Anesthetic agent micro and nano particles, and methods of making and using the same

ABSTRACT

Polymeric particles and scaffolds containing anesthetic agents, their use for sustained local delivery of anesthetic agents, reduction of pain killer addiction and addiction risk, and methods of fabricating and administering polymeric particles containing anesthetic agents are described herein.

GOVERNMENT LICENSE RIGHTS

This invention was made with government support under (identify thecontract/grant No.) awarded by (identify the Federal agency). Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

This invention describes generally polymeric particles containinganesthetic agents, their use for sustained local delivery of anestheticagents, reduction of pain killer addiction risk, and methods offabricating and administering the polymeric particles containinganesthetic agents.

BACKGROUND OF THE INVENTION

In order to provide local or regional nerve blockade for extendedperiods and control pain, clinicians use local anesthetics administeredthrough a catheter or syringe to a site where the pain is to be blocked.This requires repeated administration where the pain is to be blockedover a period of greater than one day, either as a bolus or through anindwelling catheter connected to an infusion pump. These methods havethe disadvantage of potentially causing irreversible damage to nerves orsurrounding tissues due to fluctuations in concentration and high levelsof anesthetic. In addition, anesthetic administered by these methods aregenerally neither confined to the target area, nor delivered in alinear, continuous manner. In all cases, analgesia rarely lasts forlonger than several hours.

Pain can also be controlled systemically by administration of painkiller drugs exhibiting opium or morphine-like properties generallyreferred to as opioids, or opioid agonists. However, repeated opioid useleads to potential development of tolerance, physical, and/orpsychological dependence, i.e., addiction, which is a characteristicfeature of most pain killer drugs containing opioid analgesics. Despiteall attempts to diminish the potential for abuse, the misuse and abuseof opioid pharmaceutical products continues to increase, and there is agrowing need for novel and effective methods and compositions to deterabuse of opioid pharmaceutical products.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a drug delivery particle orscaffold including a polymer matrix and an anesthetic agent. In someembodiments, the anesthetic agent is benzocaine, chloroprocaine,cocaine, cyclomethycaine, dimethocaine, piperocaine, propoxycaine,procaine, proparacaine, tetracaine, articaine, bupivacaine, cinchocaine,etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine,ropivacaine, or trimecaine. In one embodiment, the anesthetic agent islidocaine. In one embodiment, the anesthetic agent is bupivacaine. Inone embodiment, the anesthetic agent is ropivacaine. In someembodiments, the anesthetic agent is suspended or dissolved in thepolymer matrix. In some embodiments, the polymer matrix includes abioerodible polymer. In some embodiments, the polymer matrix includes apoly(alpha-hydroxy-acid) polymer or copolymer. In one embodiment, thepolymer matrix includes a poly(lactic acid) polymer (PLA). In oneembodiment, the polymer matrix includes a poly(glycolic acid) polymer(PGA). In one embodiment, the polymer matrix includes apoly(lactic-co-glycolic acid) polymer (PLGA). In one embodiment, thepolymer matrix includes a poly(vinyl alcohol) polymer (PVA). In someembodiments, the size of the particle is less than 1 μm. In someembodiments, the drug delivery scaffold further includes a hydrogel.

In one embodiment, the invention relates to a method of delivering ananesthetic agent to a subject in need thereof, the method includingadministering to the subject one or more drug delivery particles, or adrug delivers scaffold. In some embodiments, the drug deliveryparticles, or the drug delivery scaffold, include a polymer matrix andan anesthetic agent. In some embodiments the anesthetic agent isbenzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine,piperocaine, propoxycaine, procaine, proparacaine, tetracaine,articaine, bupivacaine, cinchocaine, etidocaine, levobupivacaine,lidocaine, mepivacaine, prilocaine, ropivacaine, or trimecaine. In someembodiments, after administration of the drug delivery particles, or ofthe drug delivery scaffold, the polymer matrix is gradually bioerodedand the anesthetic agent is sustainably released. In some embodiments,the anesthetic agent is sustainably released for between 1 hour and 6hours, between 3 hours and 12 hours, between 9 hours and 24 hours,between 12 hours and 48 hours, between 1 day and 3 days, between 2 daysand 1 week, between 1 week and 2 weeks, or longer than 2 weeks. In someembodiments, administration of the drug delivery particles or drugdelivery scaffold is local. In some embodiments, administration of thedrug delivery particles or drug delivery scaffold is parenteral. In someembodiments, administration of the drug delivery particles or drugdelivery scaffold is intramuscular, intradermal, subcutaneous, orsubmucosal. In some embodiments, the anesthetic agent is sustainablyreleased locally at or near the site of a wound or medical procedure.

In one embodiment, the invention relates to a method of reducing thedose of a pain killer prescribed to a subject in need thereof, themethod including administering to the subject one or more drug deliveryparticles, or a drug delivery scaffold. In some embodiments, the drugdelivery particles or the drug delivery scaffold include a polymermatrix and an anesthetic agent. In some embodiments, the anestheticagent is benzocaine, chloroprocaine, cocaine, cyclomethycaine,dimethocaine, piperocaine, propoxycaine, procaine, proparacaine,tetracaine, articaine, bupivacaine, cinchocaine, etidocaine,levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, ortrimecaine. In some embodiments, after administration of the drugdelivery particles or the drug delivery scaffold, the polymer matrix isgradually bioeroded and the anesthetic agent is sustainably released. Insome embodiments, the dose of pain killer is reduced by about 1%, about2.5%, about 5%, about 7.5%, about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,about 95%, about 99%, or about 100%. In some embodiments, the painkiller is an opioid. In some embodiments, the anesthetic agent issustainably released for between 1 hour and 6 hours, between 3 hours and12 hours, between 9 hours and 24 hours, between 12 hours and 48 hours,between 1 day and 3 days, between 2 days and 1 week, between 1 week and2 weeks, or longer than 2 weeks. In some embodiments, administration ofthe drug delivery particles or drug delivery scaffold is local. In someembodiments, administration of the drug delivery particles or drugdelivery scaffold is parenteral. In some embodiments, administration ofthe drug delivery particles or drug delivery scaffold is intramuscular,intradermal, subcutaneous, or submucosal. In some embodiments, theanesthetic agent is sustainably released locally at or near the site ofa wound or medical procedure.

In one embodiment, the invention relates to a method of reducingaddiction, or the risk of addiction, to a pain killer in a subject inneed thereof, the method including administering to the subject one ormore drug delivery particles, or a drug delivery scaffold. In someembodiments, the drug delivery particles, or the drug delivery scaffold,include a polymer matrix and an anesthetic agent. In some embodiments,the anesthetic agent is benzocaine, chloroprocaine, cocaine,cyclomethycaine, dimethocaine, piperocaine, propoxycaine, procaine,proparacaine, tetracaine, articaine, bupivacaine, cinchocaine,etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine,ropivacaine, or trimecaine. In some embodiments, after administrationthe polymer matrix is gradually bioeroded and the anesthetic agent issustainably released. In some embodiments, the addiction, or the risk ofaddiction, to a pain killer is reduced by about 1%, about 2.5%, about5%, about 7.5%, about 10%, about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 99%, or about 100%, compared to the base line addiction or risk ofaddiction. In some embodiments, the base line addiction or risk ofaddiction is measured in the same subject, in a different subject, or ina population of subjects. In some embodiments, the pain killer is anopioid. In some embodiments, the anesthetic agent is sustainablyreleased for between 1 hour and 6 hours, between 3 hours and 12 hours,between 9 hours and 24 hours, between 12 hours and 48 hours, between 1day and 3 days, between 2 days and 1 week, between 1 week and 2 weeks,or longer than 2 weeks. In some embodiments, administration of the drugdelivery particles or drug delivery scaffold is local. In someembodiments, administration of the drug delivery particles or drugdelivery scaffold is parenteral. In some embodiments, administration ofthe drug delivery particles or drug delivery scaffold is intramuscular,intradermal, subcutaneous, or submucosal. In some embodiments, theanesthetic agent is sustainably released locally at or near the site ofa wound or medical procedure.

In one embodiment, the invention relates to a method of forming drugdelivery particles, or a drug delivery scaffold, the particles or thescaffold including a polymer matrix and an anesthetic agent, the methodincluding the steps of providing a template having one or more recesses,and filing the recesses with a composition comprising the anestheticagent. In some embodiments, the anesthetic agent is benzocaine,chloroprocaine, cocaine, cyclomethycaine, dimethocaine, piperocaine,propoxycaine, procaine, proparacaine, tetracaine, articaine,bupivacaine, cinchocaine, etidocaine, levobupivacaine, lidocaine,mepivacaine, prilocaine, ropivacaine, or trimecaine. In someembodiments, a substantial portion of the composition tilling a recessforms a drug delivery particle. In some embodiments, the method offorming drug delivery particles, or a drug delivery scaffold, furtherincludes the step of separating the drug delivery particles from thetemplate. In some embodiments, the template is dissolvable in a fluid,and the method further includes the steps of placing the templateincluding formed drug delivery particles in an amount of fluid,dissolving the template, and collecting the drug delivery particles. Insome embodiments, the template includes a hydrogel. In some embodiments,the hydrogel includes gelatin. In some embodiments, the templateincludes a poly(vinyl alcohol) polymer (PVA). In some embodiments, thepolymer matrix includes a poly(lactic acid) polymer (PLA), apoly(glycolic acid) polymer (PGA), a poly(lactic-co-glycolic acid)polymer (PLGA), or a poly(vinyl alcohol) polymer (PVA).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates generally to sustainable release drug deliveryparticles and scaffolds, and methods of making and using drug deliveryparticles and scaffolds. The particles and scaffolds disclosed includebiodegradable and/or bioerodible polymers, which degrade onceadministered to a subject, while at the same time releasing the includeddrug. In some embodiments, at least 50% of the polymer degrades intoresidues, preferably non-toxic residues, which are subsequently removedby the body within a period of one week, two weeks, or the like.Polymers useful in the invention include polyanhydrides, polylacticacid-glycolic acid copolymers, polyorthoesters. In some embodiments,polylactic acid-glycolic acid copolymers are preferred. Localanesthetics are incorporated into the polymer using a method that yieldsa uniform dispersion, for example solubilization. Dispersion of a finepowder of anesthetic agent in the mass of the polymer can also be used.In some embodiments, sustained release can be attained not only bycontrolling the rate of polymer matrix bioerosion, but also byincorporation of a glucocorticoid into the polymeric matrix, or byco-administration of the glucocorticoid with the particles or scaffold.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entireties.

Definitions

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “In vitro” refers to an event that takes places outside of asubject's body. In vitro assays encompass cell-based assays in whichcells alive or dead are employed and may also encompass a cell-freeassay in which no intact cells are employed.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or combination of compounds as describedherein that is sufficient to effect the intended application including,but nor limited to, disease treatment. A therapeutically effectiveamount may vary depending upon the intended application (in vitro or invivo), or the subject and disease condition being treated (e.g., theweight, age and gender of the subject), the severity of the diseasecondition, the manner of administration, etc. which can readily bedetermined by one of ordinary skill in the art. The term also applies toa dose that will induce a particular response in target cells (e.g.,reduction of pain signaling). The specific dose will vary depending onthe particular anesthetic agents and drug delivery particles orscaffolds chosen, the dosing regimen to be followed, whether theanesthetic agent is administered in combination with other compounds,timing of administration, the tissue to which it is administered, andthe physical delivery system in which the compound is carried.

A “therapeutic effect” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit. A prophylactic effectincludes delaying or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, or any combination thereof.

As used herein, the terms “treat,” “treatment,” and/or “treating” mayrefer to the management of a disease, disorder, or pathologicalcondition, risk thereof, or symptom thereof, with the intent to cure,ameliorate, stabilize, prevent, and/or control the disease, disorder,pathological condition, risk thereof, or symptom thereof. Regardingcontrol of the disease, disorder, pathological condition, or riskthereof, more specifically, “control” may include the absence ofcondition progression, as assessed by the response to the methodsrecited herein, where such response may be complete (e.g., placing thedisease in remission) or partial (e.g., lessening or ameliorating anysymptoms associated with the condition).

The terms “QD,” “qd,” or “q.d.” mean quaque die, once a day, or oncedaily. The terms “BID,” “bid,” or “b.i.d.” mean bis in die, twice a day,or twice daily. The terms “TID,” “tid,” or “t.i.d.” mean ter in die,three times a day, or three times daily. The terms “QID,” “qid,” or“q.i.d.” mean quater in die, four times a day, or four times daily.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Preferred inorganic acids from whichsalts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.Preferred organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, andsalicylic acid. Pharmaceutically acceptable base addition salts can beformed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchange resins. Specific examples include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts.

The term “cocrystal” refers to a molecular complex derived from a numberof cocrystal formers known in the art. Unlike a salt, a cocrystaltypically does not involve hydrogen transfer between the cocrystal andthe drug, and instead involves intermolecular interactions, such ashydrogen bonding, aromatic ring stacking, or dispersive forces, betweenthe cocrystal former and the drug in the crystal structure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” is intended to include any and all solvents, dispersionmedia, coatings, antibacterial and antifungal agents, isotonic andabsorption delaying agents, and inert ingredients. The use of suchpharmaceutically acceptable carriers or pharmaceutically acceptableexcipients for active pharmaceutical ingredients is well known in theart. Except insofar as any conventional pharmaceutically acceptablecarrier or pharmaceutically acceptable excipient is incompatible withthe active pharmaceutical ingredient, its use in the therapeuticcompositions of the invention is contemplated. Additional activepharmaceutical ingredients, such as other drugs, can also beincorporated into the described compositions and methods.

“Prodrug” is intended to describe a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers the advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, e.g., Bundgaard, H., Design of Prodrugs (1985) (Elsevier,Amsterdam). The term “prodrug” is also intended to include anycovalently bonded carriers, which release live active compound in vivowhen administered to a subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to yield the active parentcompound. Prodrugs include, for example, compounds wherein a hydroxy,amino, or mercapio group is bonded to any group that, when the prodrugof the active compound is administered to a mammalian subject, cleavesto form a free hydroxy, free amino, or free mercapto group,respectively. Examples of prodrugs include, but are not limited to,acetates, formates, and benzoate derivatives of an alcohol, variousester derivatives of a carboxylic acid, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound.

Unless otherwise slated, the chemical structures depicted herein areintended to include compounds which differ only in the presence of oneor more isotopically enriched atoms. For example, compounds where one ormore hydrogen atoms is replaced by deuterium or tritium, or wherein oneor more carbon atoms is replaced by ¹³C- or ¹⁴C-enriched carbons, arewithin the scope of this invention.

When ranges are used herein to describe, for example, physical orchemical properties such as, but not limited to, amounts percentages,doses, molecular weights, or chemical formulae, all combinations andsubcombinations of ranges and specific embodiments therein are intendedto be included. Use of the term “about” when referring to a number or anumerical range means that the number or numerical range referred to isan approximation within experimental variability (or within statisticalexperimental error), and thus the number or numerical range may vary.The variation can be from 0% to 15%, from 0% to 10%, from 0% to 5%, orthe like, of the stated number or numerical range.

The term “comprising,” and related terms such as “comprise” or“comprises,” or “having” or “including,” includes those embodiments suchas, for example, an embodiment of any composition of matter, method, orprocess that “consist of” or “consist essentially of” the describedfeatures.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space—i.e., having a different stereochemical configuration.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate. “Diastereoisomers” are stereoisomers that have atleast two asymmetric atoms, but which are not mirror-images of eachother. The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon can be specified by either (R) or(S). Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds described herein containone or more asymmetric centers and can thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that can be defined, interms of absolute stereochemistry, as (R) or (S). The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible isomers, including racemic mixtures, optically pureforms and intermediate mixtures. Optically active (R)- and (S)-isomerscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers.

“Solvate” refers to a compound in physical association with one or moremolecules of a pharmaceutically acceptable solvent.

Compounds included in the invention also include crystalline andamorphous forms of those compounds, including, for example, polymorphs,pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof. “Crystalline form” and“polymorph” are intended to include all crystalline and amorphous formsof the compound, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms, as well as mixturesthereof, unless a particular crystalline or amorphous form is referredto.

Drug delivery particles and scaffolds of the present disclosure,including any of their ingredients, exhibit “biocompatibility” or are“biocompatible,” meaning that the compositions are compatible withliving tissue or a living system by not being substantially toxic,injurious, or physiologically reactive and not causing immunologicalrejection. The term “biocompatible” encompasses the terms“bioabsorbable,” “bioresorbable,” “biodegradable,” and “bioerodible,”which are defined herein.

Drug delivery particles and scaffolds of the present disclosure,including any of their ingredients, may be “bioabsorbable,”“bioresorbable,” “biodegradable,” and/or bioerodible. As used herein,the terms “bioabsorbable” refers to materials or substances thatdissipate upon implantation within a body, independent of whichmechanisms by which dissipation can occur, such as dissolution,degradation, absorption, and excretion. As used herein, the term“bioresorbable” means capable of being absorbed by the body. As usedherein, the terms “biodegradable” and/or “bioerodible” refer tomaterials which can decompose under physiological conditions intobyproducts. Such physiological conditions include, for example,hydrolysis, i.e., decomposition via hydrolytic cleavage, enzymaticcatalysis, or enzymatic degradation, mechanical interactions, and thelike. As used herein, the term “biodegradable” also encompasses the term“bioresorbable”, which describes a material or substance that decomposesunder physiological conditions to break down to products that undergobioresorption into the host-organism, namely, become metabolites of thebiochemical systems of the host organism. As used herein, the terms“bioresorbable” and “bioresorption” encompass processes such ascell-mediated degradation, enzymatic degradation, hydrolytic degradationof the bioresorbable polymer, and/or elimination of the bioresorbablepolymer from living tissue as will be appreciated by the person skilledin the art. The degree of biodegradation, bioabsorption, bioresorption,and/or bioerosion may be modified and/or controlled by, for example,adding one or more agents to compositions described herein that retardbiodegradation, bioabsorption, bioresorption, and/or bioerosion. Inaddition, the degree of biodegradation, bioabsorption, bioresorption,and/or bioerosion may be modified and/or controlled by increasing ordecreasing the degree of polymeric cross-linking present in thepolymeric materials described herein. For example, the rate ofbiodegradation, bioabsorption, bioresorption, and/or bioerosion of thecompositions described here may be increased by reducing the amount ofcrosslinking in the polymeric materials described herein. Alternatively,the rate of biodegradation, bioabsorption, bioresorption, and/orbioerosion of the drug delivery particles and scaffolds of the presentdisclosure, including any of their ingredients, described here, may bedecreased by increasing the amount of crosslinking in the polymericmaterials described herein.

For the avoidance of doubt, it is intended herein that particularfeatures, e.g., integers, characteristics, values, uses, diseases,formulae, compounds, or groups described in conjunction with aparticular aspect, embodiment, or example of the invention, are to beunderstood as applicable to any other aspect, embodiment or exampledescribed herein unless incompatible therewith. Thus such features maybe used where appropriate in conjunction with any of the definition,claims or embodiments defined herein. All of the features disclosed inthis specification (including any accompanying claims, abstract anddrawings), and/or all of the steps of any method or process sodisclosed, may be combined in any combination, except combinations whereat least some of the features and/or steps are mutually exclusive. Theinvention is not restricted to any details of any disclosed embodiments.The invention extends to any novel one, or novel combination, of thefeatures disclosed in this specification (including any accompanyingclaims, abstract and drawings), or to any novel one, or any novelcombination, of the steps of any method or process so disclosed.

Anesthetic Agents

Anesthetic agents useful in the invention are generally known in theart. The invention envisions however the use of any anesthetic agent,including anesthetic agents not yet known. In some embodiments, theanesthetics are local anesthetic, i.e., drugs which provide localnumbness or pain relief. A number of different local anesthetics can beused, including benzocaine, chloroprocaine, cocaine, cyclomethycaine,dimethocaine, piperocaine, propoxycaine, procaine, proparacaine,tetracaine, articaine, bupivacaine, cinchocaine, etidocaine,levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, ortrimecaine. In some embodiments, the local anesthetic is used the formof a salt, for example, the hydrochloride, bromide, acetate, citrate, orsulfate of the anesthetic agent. In some embodiments, compared to thefree base form of these drugs, the more hydrophilic hydrochloride saltdisplays longer and denser nerve block, more complete release frompolymer matrices, slower clearance from the targeted nerve area, andless encapsulation. Bupivacaine is a long acting and potent localanesthetic, providing other advantages such as sufficient sensoryanesthesia without significant motor blockage, lower toxicity, and wideavailability.

In some embodiments, the anesthetic agent is an ester group anestheticagent, for example, benzocaine, chloroprocaine, cocaine,cyclomethycaine, dimethocaine (larocaine), piperocaine, propoxycaine,procaine (novocaine), proparacaine, or tetracaine (amethocaine).Representative examples of ester group anesthetic agents are listed inTable 1.

TABLE 1 Ester Group Anesthetic Agents

Benzocaine

Chloroprocaine

Cocaine

Cyclomethycaine

Dimethocaine

Piperocaine

Propoxycaine

Procaine

Proxymetacaine

Tetracaine

In some embodiments, the anesthetic agent is an amide group anestheticagent, for example, articaine, bupivacaine, cinchocaine (dibucaine),etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine,prilocaine, ropivacaine, or trimecaine. Representative examples of amidegroup anesthetic agents are listed in Table 2.

TABLE 2 Amide Group Anesthetic Agents

Articaine

Bupivacaine

Cinchocaine

Etidocaine

Levobupivacaine

Lidocaine

Mepivacaine

Prilocaine

Ropivacaine

Trimecaine

Polymer Matrix

The polymers used to make the particles and scaffolds of the inventionare for example polyanhydrides, polylactic acid-glycolic acidcopolymers, or polyorthoesters. In some embodiments, the polymer matrixincludes a poly(alpha-hydroxy-acid) polymer or copolymer. In oneembodiment, the polymer matrix includes a poly(lactic acid) polymer(PLA). In one embodiment, the polymer matrix includes a poly(glycolicacid) polymer (PGA). In one embodiment, the polymer matrix includes apoly(lactic-co-glycolic acid) polymer (PLGA). In one embodiment, thepolymer matrix includes a poly(vinyl alcohol) polymer (PV). The polymersused are biodegradable and bioerodible. In some embodiments, polylacticacid-glycolic acid copolymers are preferred.

The polymers used are generally biocompatible. The polymers used degradein vivo over a period of less than a year, with at least 50% of thepolymer degrading within six months or less. More preferably, thepolymer will degrade significantly within a month, with at least 50% ofthe polymer degrading into non-toxic residues which are removed by thebody, and 100% of the drug being released within a certain period oftime, for example between 1 hour and 6 hours, between 3 hours and 12hours, between 9 hours and 24 hours, between 12 hours and 48 hours,between 1 day and 3 days, between 2 days and 1 week, between 1 week and2 weeks, or longer than 2 weeks.

Polymers degrade by hydrolysis, by surface erosion, or by bulk erosion.In some embodiments, surface erosion is preferred, as it affords notonly a sustained drug release, but also a release which is, in someembodiments, linear or quasi-linear.

When using a poly(lactic-co-glycolic acid) polymer (PLGA), the weightratio of lactic acid to glycolic acid can be adjusted to achieve variousend parameters. In some embodiments, the weight ratio of lactic acid toglycolic acid is between about 99:1 to about 1:99, between about 95:5 toabout 5:95, between about 90:10 to about 10:90, between about 75:25 toabout 25:75, between about 65:35 to about 35:65, or between about 55:45to about 45:55. In some embodiments, the w/w ratio between lactic acidto glycolic acid is between about 99:1 to about 55:45, between about95:5 to about 45:55, between about 90:10 to about 35:65, between about75:25 to about 15:85, between about 65:35 to about 10:90, or betweenabout 55:45 to about 1:99. In an embodiment, the weight ratio of lacticacid to glycolic acid is about 99:1, about 98:2, about 97:3, about 96:4,about 95:5, about 94:6, about 93.7, about 92:8, about 91:9, about 90:10,about 89:11, about 88:12, about 87:13, about 86:14, about 85:15, about84:16, about 83:17, about 82:18, about 81:19, about 80:20, about 79:21,about 78:22, about 77:23, about 76:24, about 75:25, about 74:26, about73:27, about 72:28, about 71:29, about 70:30, about 69:31, about 68:32,about 67:33, about 66:34, about 65:35, about 64:36, about 63:37, about62:38, about 61:39, about 60:40, about 59:41, about 58:42, about 57:43,about 56:44, about 55:45, about 54:46, about 53:47, about 52:48, about51:49, about 50:50, about 49:51, about 48:52, about 47:53, about 46:54,about 45:55, about 44:56, about 43:57, about 42:58, about 41:59, about40:60, about 39:61, about 38:62, about 37:63, about 36:64, about 35:65,about 34:66, about 33:67, about 32:68, about 31:69, about 30:70, about29:71, about 28:72, about 27:73, about 26:74, about 25:75, about 24:76,about 23:77, about 22:78, about 21:79, about 20:80, about 19:81, about18:82, about 17:83, about 16:84, about 15:85, about 14:86, about 13:87,about 12:88, about 11:89, about 10:90, about 9:91, about 8:92, about7:93, about 6:94, about 5:95, about 4:96, about 3:97, about 2:98, orabout 1:99. In some embodiments, the weight ratio of lactic acid toglycolic acid is no more than 4:1 (i.e., 80% or less lactic acid to 20%or more glycolic acid by weight). Other polymers include proteinpolymers such as gelatin and fibrin, and polysaccharides such aschitosan and/or hyaluronic acid.

Methods of Making

In some embodiments, the drug delivery particles and scaffolds can bemade using the hydrogel template method, and/or the PVA template method.The methods are described in: Acharya et al., 2010, Journal ofControlled Release, 146, 201-206; Shin et al., BiomedicalNanotechnology: Methods and Protocols, Methods in Molecular Biology,vol. 1370, Chapter 19, DOI 10.1007/978-1-4939-6840-4_19; Acharya et al.,Biomedical Nanotechnology: Methods and Protocols, Methods in MolecularBiology, vol. 726, Chapter 12, DOI 10.1007/978-1-61779-052-2_12; andAcharya et al., 2010, Journal of Controlled Release, 141, 314-319;incorporated in their entireties herein.

In some embodiments, the methods of making the drug delivery particlesand scaffolds of the invention rely on the use of template including asubstantially flat surface decorated with a series of protuberances. Theprotuberances serve as shaping sub-templates for the final shape andsize of the drug delivery particles. In some embodiments, the templatecan be made from a silicon polymer, and the protuberances can havevarious shapes, e.g., cylindrical, prismatic, conical, and the like. Theprotuberances can be sized on a nano scale or on a micro scale, and canhave a height from tens or hundreds of nanometers, to tens or hundredsof micrometers. The protuberances can have dimensions on the three axisof space, for example a diameter or a sectional axis, similarly sized tothe height, i.e., from tens or hundreds of nanometers, to tens orhundreds of micrometers. In one embodiment, the protuberances arecylindrical. In some embodiments, the template is flexible. In someembodiments, the template is made from a silicon based polymer.

In some embodiments, a solution, a suspension, or a gel including apolymer, can be casted or pouted onto the template. In some embodiments,the polymer can be a mixture of proteins, for example gelatin or fibrin.In some embodiments, the polymer can be PVA. Under various conditionsdescribed in the art, the polymer, for example gelatin or PVA, coalescesto form a scaffold which can thereafter be removed from the template.The concentration of the solution can be adjusted in order to afford ascaffold with various degrees of elasticity and mechanical strength.Once coalesced, the scaffold is removed, for example peeled, from thetemplate. The scaffold is shaped as the negative image of the template.For example, if the template includes cylindrical protuberances, thescaffold includes cylindrical recesses. The size of the scaffoldrecesses substantially mirrors the size of the template protuberances.The recesses are sized on a nano scale or on a micro scale, and have adepth from tens or hundreds of nanometers, to tens or hundreds ofmicrometers. The recesses have dimensions on the three axis of space,for example a diameter or a sectional axis, from tens or hundreds ofnanometers, to tens or hundreds of micrometers. In one embodiment, therecesses are cylindrical.

In some embodiments, the depth of the scaffold recesses is from about250 nm to about 500 nm, from about 450 nm to about 750 nm, from about650 nm to about 1 μm, from about 850 nm to about 2.5 μm, from about 1 μmto about 10 μm, from about 5 μm to about 75 μm, from about 50 μm toabout 250 μm, from about 100 μm to about 500 μm, from about 456 μm toabout 750 μm, or from about 500 μm to about 1 mm.

In some embodiments, the diameter of the scaffold recesses is from about250 nm to about 500 nm, from about 450 nm to about 750 nm, from about650 nm to about 1 μm, from about 850 nm to about 2.5 μm, from about 1 μmto about 10 μm, from about 5 μm to about 75 μm, from about 50 μm toabout 250 μm, from about 100 μm to about 500 μm, from about 450 μm toabout 750 μm, or from about 500 μm to about 1 mm.

In some embodiments, any end to end dimension of the scaffold recessesis from about 250 nm to about 500 nm, from about 450 nm to about 750 nm,from about 650 nm to about 1 μm, from about 850 nm to about 2.5 μm, fromabout 1 μm to about 10 μm, from about 5 μm to about 75 μm, from about 50μm to about 250 μm, from about 100 μm to about 500 μm, from about 450 μmto about 750 μm, or from about 506 μm to about 1 mm.

The scaffold recesses are thereafter filled with a composition includingan anesthetic agent. The composition can be a solution, a suspension, agel, or the like. The anesthetic agent composition is cast, poured, orotherwise dispose on the side of the scaffold having recesses, and theexcess composition is removed by various methods, for example by adoctor blade device. The composition may include a solvent, and/or apolymer. In some embodiments, the polymer can be the same polymer asused in the scaffold. In some embodiments, the polymer can be differentthan the polymer used in the scaffold. In some embodiments, the polymerin the composition includes a poly(alpha-hydroxy-acid) polymer orcopolymer. In one embodiment, the polymer in the composition includes apoly(lactic acid) polymer (PLA). In one embodiment, the polymer in thecomposition includes a poly(glycolic acid) polymer (PGA). In oneembodiment, the polymer in the composition includes apoly(lactic-glycolic acid) polymer (PLGA). In one embodiment, thepolymer in the composition includes a poly(vinyl alcohol) polymer (PVA).In some embodiments, the composition includes a protein mixture, forexample gelatin of fibrin. The composition generally coalesces to fill asubstantial portion of the totality of scaffold recesses with a particleincluding the anesthetic agent. The scaffold having a substantiallyportion of the totality of recesses substantially filled with particlesincluding an anesthetic agent can be used as such. The scaffold can forexample be cut into a particular shape and/or size, and used as animplant. In one embodiment, the scaffold can be cut into circular,square, triangular, trapezoidal, rectangular, or the like, patches.

In some embodiments, the materials in the scaffold are generally able todissolve, while the materials in the scaffold recesses, i.e., thematerials making a particle, are not, or have a lesser degree ofsolvability than the scaffold material. Thus the scaffold can besubmerged into various solutions known in the art, where the majority ofthe materials making the scaffold dissolve, leaving the particles in thescaffold recesses undissolved. The particles are thereafter collected asa multitude of drug delivery particles including a polymer matrix and ananesthetic agent. The resulting particles are obtained in a variety ofshapes, for example cylindrical, prismatic, or the like. The resultingparticles are obtained in a variety of sizes, depending on the size ofthe protuberances and recesses described here relative to the making ofthe drug delivery particles. The particles may be generally consistentin size or may be part of a distribution (e.g., formed from anemulsion). In some embodiments, any end to end dimension of theparticles is from about 250 nm to about 500 nm, from about 450 nm toabout 750 nm, from about 650 nm to about 1 μm, from about 850 nm toabout 2.5 μm, from about 1 μm to about 10 μm, from about 5 μm to about75 μm, from about 50 μm to about 250 μm, from about 100 μm to about 500μm, from about 450 μm to about 750 μm, or from about 500 μm to about 1mm. In some embodiments, any transversal, axial, or otherwise end to enddimension of the particles is about 50 nm, about 100 nm, about 150 nm,about 200 nm, about 250 nm, about 300 nm, about 350 nm, about 400 nm,about 450 nm, about 500 nm, about 550 nm, about 600 nm, about 650 nm,about 700 nm, about 750 nm about 800 nm, about 850 nm, about 900 nm,about 950 nm, or about 1 μm. In some embodiments, any transversal,axial, or otherwise end to end dimension of the particles is about 50μm, about 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300μm, about 350 μm, about 400 μm, about 450 μm, about 500 μm, about 550μm, about 600 μm, about 650 μm, about 700 μm, about 750 μm, about 800μm, about 850 μm, about 900 μm, about 950 μm, or about 1 mm.

Pharmaceutical Composition

In one embodiment, the invention provides a pharmaceutical compositionfor use in the treatment of the diseases and conditions describedherein. In a preferred embodiment, the invention provides pharmaceuticalcompositions, including those described below, for use in the treatmentof pain, by local administration. In some embodiments, the inventionrelates to a pharmaceutical composition including one or more anestheticagents, or pharmaceutically acceptable salts, solvates, hydrates,cocrystals, or prodrugs thereof. In some embodiments, the anestheticagent is formulated into a drug delivery particle, or a drug deliveryscaffold. In some embodiments, the pharmaceutical compositions furtherinclude a physiologically compatible carrier medium.

The pharmaceutical compositions are typically formulated to provide atherapeutically effective amount of an anesthetic agent, or a fragment,derivative, conjugate, variant, radioisotope-labeled complex, orbiosimilar thereof, or pharmaceutically acceptable salts, prodrugs,solvates, or hydrates thereof, as the active ingredients. Where desired,the pharmaceutical compositions contain a pharmaceutically acceptablesalt and/or coordination complex of one or more of the activeingredients. Typically, the pharmaceutical compositions also compriseone or more pharmaceutically acceptable excipients, carriers, includinginert solid diluents and fillers, diluents, including sterile aqueoussolution and various organic solvents, permeation enhancers,solubilizers and adjuvants.

In some embodiments, the concentration of any one anesthetic agentprovided in a pharmaceutical composition of the invention, for examplein a drug delivery particle or a drug delivery scaffold is independentlyless than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%,0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w,w/v, or v/v of the pharmaceutical composition.

In some embodiments, the concentration of any one anesthetic agentprovided in a pharmaceutical composition of the invention, for examplein a drug delivery particle or a drug delivery scaffold, isindependently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25%, 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v of thepharmaceutical composition.

In some embodiments, the concentration of any one anesthetic agentprovided in a pharmaceutical composition of the invention, for examplein a drug delivery particle or a drug delivery scaffold, isindependently in the range from about 0.0001% to about 50%, from about0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% toabout 29%, from about 0.03% to about 28%, from about 0.04% to about 27%,from about 0.05% to about 26%, from about 0.06% to about 25%, from about0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% toabout 22%, from about 0.1% to about 21%, from about 0.2% to about 20%,from about 0.3% to about 19%, from about 0.4% to about 18%, from about0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% toabout 15%, from about 0.8% to about 14%, from about 0.9% to about 12%,or from about 1% to about 10% w/w, w/v, or v/v of the pharmaceuticalcomposition.

In some embodiments, the concentration of any one anesthetic agentprovided in a pharmaceutical composition of the invention, for examplein a drug delivery panicle or in a drug delivery scaffold isindependently in the range from about 0.001% to about 10%, from about0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% toabout 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%,from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% toabout 0.9% w/w, w/v, or v/v of the pharmaceutical composition.

In some embodiments, the amount of anesthetic agent provided in apharmaceutical composition of the invention, for example in a doseincluding drug delivery particles, or drug delivery scaffold, isindependently equal to or less than about 10 g, about 9.5 g, about 9.0g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g,about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g,about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g,about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g,about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g,about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g,about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about0.0001 g.

Pharmaceutical Compositions for Injection

In preferred embodiments, the invention provides a pharmaceuticalcomposition for injection containing drug delivery particles or drugdelivery scaffolds according to the invention, and a pharmaceuticalexcipient suitable for injection. Components and amounts of agents inthe compositions are as described herein. The forms in which thecompositions of the present invention may be incorporated foradministration by injection include aqueous or oil suspensions, oremulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, aswell as elixirs, mannitol, dextrose, or a sterile aqueous solution, andsimilar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (andsuitable mixtures thereof), cyclodextrin derivatives, and vegetable oilsmay also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, for the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample parabens, chlorobutanol, phenol, sorbic add, and thimerosal.

Sterile injectable solutions are prepared by incorporating drug deliveryparticles or drug delivery scaffolds including an anesthetic agentdescribed here, in the required amounts, in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed bysterilization. Generally, dispersions are prepared by incorporating thevarious sterilized active ingredients into a sterile vehicle whichcontains the basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, certain desirable methodsof preparation are vacuum-drying and freeze-drying techniques whichyield a powder of the active ingredient plus any additional desiredingredient from a previously sterile-filtered solution thereof.

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for intraosseous, intraocular, epidural or intraspinaladministration. Preparations for such pharmaceutical compositions arewell-known in the art. See, e.g., Anderson, et al., eds., Handbook ofClinical Drug Data, Tenth Edition, McGraw-Hill, 2002, and Pratt andTaylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990, each of which is incorporated by referenceherein in its entirety.

Methods of Treatment

The drug delivery particles and scaffolds of the invention are used inany therapeutic indication requiring pain management. Traumaticinjuries, whether accidental or as a result of a medical procedure, canbe accordingly treated by using the drug delivery particles or scaffoldsdescribed here. When placed, for example injected, at or near the siteof a an injury, for example a cut, laceration, or surgical incision, thedrug delivery particles and scaffolds of the invention are designed tobiodegrade and sustainably deliver the anesthetic agent included. Theanesthetic agent is sustainably released for between 1 hour and 6 hours,between 3 hours and 12 hours, between 9 hours and 24 hours, between 12hours and 48 hours, between 1 day and 3 days, between 2 days and 1 week,between 1 week and 2 weeks, or longer than 2 weeks. In some embodiments,the anesthetic agent is sustainably released for about 1 hour, about 2hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours,about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours,about 21 hours, about 22 hours, about 23 hours, or about 24 hours. Insome embodiments, the anesthetic agent is sustainably released for about1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6days, about 7 days, about 8 days, about 9 days, about 10 days, about 11days, about 12 days, about 13 days, or about 14 days. In someembodiments, the anesthetic agent is sustainably released for about 1week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about6 weeks, about 7 weeks, or about 8 weeks. In some embodiments, theanesthetic agent is sustainably released for a period of time includingany combination of hours, days, and/or weeks described here.

By sustainably releasing one or more anesthetic agents, the drugdelivery particles and scaffolds described here afford a better painmanagement system, and thus result in a decrease, and in someembodiments, a complete elimination for the need of systemic painmedication. For example, even if the practitioner still prescribessystemic pain medication, for example an opioid, the drug deliveryparticles and scaffolds described here afford a reduction in the dose ofpain killer prescribed to the subject or patient in need thereof. Insome embodiments, the dose of pain killer is reduced by about 1%, about2.5%, about 5%, about 7.5%, about 10%, about 15%, about 20%, about 25%,about 30%, about 75%, about 40%, about 45%, about 50%, about 55%, about60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,about 95%, about 99%, or about 100%. In some embodiments, the dose ofpain killer is reduced by about 1%, about 2%, about 3%, about 4%, about5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%,about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%,about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%,about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%,about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%,about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%,about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%,about 97%, about 98%, about 99%, or about 100%. In some embodiments, thedose of pain killer is completely eliminated. In some embodiments, thepain killer is an opioid.

By reducing the dose of pain medication needed or required, the use ofdrug delivery particles and scaffolds described here result in areduction of any existing addiction to a pain killer, or a reduction inthe risk of acquiring such addiction. In some embodiments, the painkiller is an opioid. In some embodiments, the addiction, or the risk ofaddiction, to a pain killer is reduced by about 1%, about 2.55%, about5%, about 7.5%, about 10%, about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 99%, or about 100%, compared to the base line addiction or risk ofaddiction. In some embodiments, the addiction, or the risk of addiction,to a pain killer is reduced by about 1%, about 2%, about 3%, about 4%,about 5%, about 6%, about 7*%, about 8%, about 9%, about 10%, about 11%,about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%,about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%,about 38%, about 39%, about 49%, about 41%, about 42%, about 43%, about44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%,about 51%, about 52%, about 55%, about 54%, about 55%, about 56%, about57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%,about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%,about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%,about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about96%, about 97%, about 98%, about 99%, or about 100%, compared to thebase line addiction or risk of addiction. The base line addiction orrisk of addiction is measured in the same subject, in a differentsubject, or in a population of subjects.

Methods of Administration

Administration of a composition including drug delivery particles ordrug delivery scaffolds according to the invention, can be effected byany method that enables delivery of the compounds to the site of action.These methods include parenteral injection (including subcutaneous,submucosal, intramuscular, intravascular, intraperitoneal, or infusion),topical (e.g., transdermal application), rectal administration, vialocal delivery by catheter or stent. The compositions thereof can alsobe administered intraadiposally or intrathecally. Exemplary parenteraladministration forms include solutions or suspensions of active compoundin sterile aqueous solutions, for example, aqueous propylene glycol ordextrose solutions. Such dosage forms can be suitably buffered, ifdesired.

In some embodiments, formulations including the drug delivery particlesand scaffolds described herein are locally administered, for example byinjection or implantation, at or near the site of a wound or surgicalprocedure. Methods and protocols for determining the best location forlocal delivery are known in the art.

The invention also provides kits. The kits include drug deliveryparticles or drug delivery scaffolds according to the invention, orpharmaceutical compositions thereof, either alone or in combination, insuitable packaging, and written material that can include instructionsfor use, discussion of clinical studies, and listing of side effects.Such kits may also include information, such as scientific literaturereferences, package insert materials, clinical trial results, and/orsummaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. The kit may further contain another activepharmaceutical ingredient.

Suitable packaging and additional articles for use (e.g., measuring cupfor liquid preparations, foil wrapping to minimize exposure to air, andthe like) are known in the art and may be included in the kit. Kitsdescribed herein can be provided, marketed and/or promoted to healthproviders, including physicians, nurses, pharmacists, formularyofficials, and the like. Kits may also, in some embodiments, be marketeddirectly to the consumer.

In some embodiments, the invention provides a kit comprising acomposition comprising a therapeutically effective amount of anestheticagents, as formulated into drug delivery particles or scaffolds,according to the invention, or anesthetic agents, conjugates, variants,radioisotope-labeled complexes, pharmaceutically acceptable salts,solvates, hydrates, cocrystals, or prodrugs thereof, similarlyformulated into drug delivery particles or scaffolds described here.Those compositions are typically pharmaceutical compositions.

The kits described above are preferably for use in the treatment of thediseases and conditions described herein. In a preferred embodiment, thekits are for use in the treatment of pain, or in the treatment of painmedication addiction or risk of acquiring addiction.

Combinations of Anesthetic Agents with Other Active PharmaceuticalIngredients

The anesthetic agents described here, including the drug deliveryparticles and scaffolds described here, can also be co-administered withadditional chemotherapeutic active pharmaceutical ingredients, forexample anti-inflammatories such as glucocorticoids, that are useful toprolong in vivo sustainable release. Glucocorticoids includedexamethasone, cortisone, prednisone, and others routinely administeredorally, or by injection. Useful loadings are from 0.01 to 30% by weight,preferably between 0.05 and 0.5%. The dosage must be low enough to avoidtoxicity. Glucocorticoids such as dexamethasone prolong release in vivo,and do not reduce the intensity of the nerve block generated by therelease of the anesthetic agent from the polymer, and do not affect therecovery of sensation and strength.

While preferred embodiments of the invention are shown and describedherein, such embodiments are provided by way of example only and are notintended to otherwise limit the scope of the invention. Variousalternatives to the described embodiments of the invention may beemployed in practicing the invention.

1. A drug delivery particle or scaffold comprising a polymer matrix andan anesthetic agent selected from the group consisting of benzocaine,chloroprocaine, cocaine, cyclomethycaine, dimethocaine, piperocaine,propoxycaine, procaine, proparacaine, tetracaine, articaine,bupivacaine, cinchocaine, etidocaine, levobupivacaine, lidocaine,mepivacaine, prilocaine, ropivacaine, and trimecaine.
 2. The drugdelivery particle or scaffold of claim 1, wherein the anesthetic agentis lidocaine, bupivacaine, or ropivacaine.
 3. The drug delivery particleor scaffold of claim 1, wherein the anesthetic agent is suspended ordissolved in the polymer matrix.
 4. The drug delivery particle orscaffold of claim 1, wherein the polymer matrix comprises a bioerodiblepolymer.
 5. The drug delivery particle or scaffold of claim 1, whereinthe polymer matrix comprises a poly(alpha-hydroxy-acid) polymer orcopolymer.
 6. The drug delivery particle or scaffold of claim 1, whereinthe polymer matrix comprises a poly(lactic acid) polymer (PLA), apoly(glycolic acid) polymer (PGA), a poly(lactic-co-glycolic acid)polymer (PLGA), or a poly(vinyl alcohol) polymer (PVA).
 7. The drugdelivery particle of claim 1, wherein the size of the particle is lessthan 1 μm.
 8. The drug delivery scaffold of claim 1, further comprisinga hydrogel. 9.-39. (canceled)